Alternative titles; symbols
HGNC Approved Gene Symbol: SLC40A1
SNOMEDCT: 719975002;
Cytogenetic location: 2q32.2 Genomic coordinates (GRCh38): 2:189,560,590-189,580,786 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 2q32.2 | Hemochromatosis, type 4 | 606069 | Autosomal dominant | 3 |
Defects in iron absorption and utilization lead to iron deficiency and overload disorders. Adult mammals absorb iron through the duodenum, whereas embryos obtain iron through placental transport. Iron uptake from the intestinal lumen through the apical surface of the polarized duodenal enterocytes is mediated by the divalent metal transporter, DMT1 (600523). A second transporter had been postulated to export iron across the basolateral surface to the circulation. Donovan et al. (2000) used positional cloning to identify the gene responsible for the hypochromic anemia of the zebrafish mutant 'weissherbst.' The gene, which they called ferroportin-1 (fpn1), encodes a multiple-transmembrane domain protein expressed in the yolk sac that was a candidate for the elusive iron transporter. Zebrafish ferroportin-1 is required for the transport of iron from maternally-derived yolk stores to the circulation and functions as an iron exporter when expressed in Xenopus oocytes.
Donovan et al. (2000) isolated mouse and human ferroportin-1 cDNAs by RT-PCR of liver and placenta, respectively. Human ferroportin-1 is a protein of 571 amino acids. A conserved sequence, predicted to form a hairpin-loop structure typical of iron response elements (IREs), was identified in the 5-prime untranslated region of the cDNAs from all 3 species. Northern blot analysis showed the highest level of expression in human placenta, liver, spleen, and kidney. In mouse, primitive erythroblasts derived from the blood islands do not express ferroportin-1, whereas the trophoblast cells of the inner placenta express high levels of ferroportin-1. In the human placenta, ferroportin-1 protein was primarily expressed in a basal location within the syncytiotrophoblasts, suggesting that it transports iron from mother to embryo. Mammalian ferroportin-1 is also expressed at the basolateral surface of duodenal enterocytes. On the basis of basolateral expression pattern of ferroportin-1 in mammalian enterocytes and the implication that ferroportin-1 is required for intestinal iron absorption and iron transport in zebrafish, Donovan et al. (2000) suggested that the protein is probably involved in iron export from enterocytes in mammals.
Iron absorption by the duodenal mucosa is initiated by uptake of ferrous Fe(II) iron across the brush border membrane and culminates in transfer of the metal across the basolateral membrane to the portal vein circulation by an unknown mechanism. Using a subtractive cloning strategy and PCR analysis, McKie et al. (2000) isolated mouse and human duodenal cDNAs encoding FPN1, which they called iron-regulated transporter-1 (IREG1). The IREG1 protein contains 10 transmembrane domains and is localized to the basolateral membrane of polarized epithelial cells. IREG1 mRNA and protein expression are increased under conditions of increased iron absorption, and the 5-prime untranslated region of the IREG1 mRNA contains a functional IRE.
By FISH, Haile (2000) mapped the SLC40A1 gene to human chromosome 2q32 and mouse chromosome 1B.
McKie et al. (2000) found that IREG1 stimulated iron efflux following expression in Xenopus oocytes. They concluded that IREG1 represents the long-sought duodenal iron export protein and is upregulated in the iron overload disease hereditary hemochromatosis (235200).
Nemeth et al. (2004) reported that hepcidin (606464) bound to ferroportin in tissue culture cells. After binding, ferroportin was internalized and degraded, leading to decreased export of cellular iron. Nemeth et al. (2004) postulated that the posttranslational regulation of ferroportin by hepcidin may complete a homeostatic loop regulating iron plasma levels and the tissue distribution of iron.
Sangokoya et al. (2013) stated that FPN expression is downregulated in an iron-dependent manner by binding of iron regulatory protein (IRP; see 100880) to the IRE in the 5-prime UTR of the FPN transcript. Using a reporter gene assay, they confirmed that FPN expression decreased during iron depletion and increased significantly during iron supplementation in human HepG2 hepatocytes. Sangokoya et al. (2013) also identified a regulatory region in the 3-prime UTR of FPN that bound the microRNA MIR485-3p (615385). MIR485-3p was induced during iron deficiency in human cell lines, and MIR485-3p binding to the 3-prime UTR of the FPN transcript repressed FPN translation, leading to increased cellular ferritin (see 134790) levels and increased cellular iron. Inhibition of MIR485-3p activity or mutation of the MIR485-3p-binding site in the FPN 3-prime UTR relieved FPN repression and led to cellular iron deficiency. IRP and MIR485-3p downregulated FPN expression in an additive manner.
Nairz et al. (2013) found that macrophages from mice lacking nitric oxide synthase-2 (NOS2; 163730) displayed reduced expression of Fpn1. Nitric oxide upregulated FPN1 expression in mouse and human cells. Nos2-null mouse macrophages had increased iron content due to reduced Fpn1 activity. Reduced Fpn1 expression allowed enhanced iron acquisition by the intracellular bacterium Salmonella typhimurium. Mice lacking Nos2 or mice in which Nos2 activity was inhibited had increased iron accumulation in spleen and spleen macrophages. Lack of nitric oxide formation resulted in impaired Nrf2 (NFE2L2; 600492) expression and, consequently, reduced Fpn1 transcription and cellular iron export. Infection of Nos2-null mice or macrophages with S. typhimurium led not only to increased iron accumulation, but also to reduced Tnf (191160), Il2 (147680), and Ifng (147570) expression and impaired pathogen control, all of which could be restored by treatment with iron chelators or overexpression of Fpn1 or Nrf2. Nairz et al. (2013) concluded that iron accumulation in Nos2-null macrophages counteracts a proinflammatory host response and that the protective effects of nitric oxide partially result from its ability to prevent iron overload in macrophages.
Zhang et al. (2018) found that ferroportin is highly abundant in mature red blood cells and that its activity is inhibited by iron supplementation and hepcidin. Additional deletion of the FPN1 gene in erythroid cells resulted in accumulation of excess intracellular iron, cellular damage, hemolysis, and increased fatality in malaria-infected mice. Fpn knockout increased non-heme iron content and intracellular ferritin levels in erythroblasts and resulted in a mild compensated anemia and extramedullary erythropoiesis. The anemia was not caused by a defect in erythroblast differentiation, but instead by the increased fragility and hemolysis of mature red blood cells, as evidenced by the 2.5-fold increase of free plasma hemoglobin after storage at 4 degrees C for 20 hours. Zhang et al. (2018) intravenously injected wildtype and Fpn knockout mice with Plasmodium yoelii, a lethal murine malaria strain. The knockout mice had 60% more parasite-infected red blood cells than wildtype mice on multiple successive days after infection, and died more rapidly after infection.
By mutation analysis of all exons, intron-exon boundaries, and the 5-prime and 3-prime untranslated region (including the IRE) of the SLC40A1 gene in a Dutch family with hemochromatosis type 4 (HFE4; 606069), Njajou et al. (2001) identified a heterozygous A-to-C transversion at nucleotide 734 in exon 5 in all affected individuals. The mutation resulted in an asn144-to-his substitution (604653.0001). The substituted asn is a highly conserved amino acid in vertebrates.
Independently, in an Italian family with autosomal dominant hemochromatosis originally reported by Pietrangelo et al. (1999), Montosi et al. (2001) mapped the disease locus responsible for autosomal dominant hemochromatosis to 2q32 and recognized ferroportin as a compelling positional candidate for the site of the mutation. They identified a mutation in the SLC40A1 gene (604653.0002). They pointed out that the distinguishing features of this disorder, in addition to autosomal dominant inheritance, is early iron accumulation in reticuloendothelial cells and a marked increase in serum ferritin before elevation of the transferrin saturation. Fleming and Sly (2001) commented that haploinsufficiency for ferroportin would (at least initially) favor low serum iron by decreasing dietary iron absorption and by impairing iron release from macrophages. This could explain the low transferrin saturations, the anemia early in life, and the sensitivity to phlebotomy observed in many of these patients. The hepatocellular iron loading might be explained by the secondary effects of the 'erythropoietic regulator' stimulating intestinal iron absorption, or possibly by ferroportin-1 haploinsufficiency in hepatocytes.
Unexplained hyperferritinemia is a common clinical finding, even in asymptomatic persons. When early-onset bilateral cataracts are also present, hereditary hyperferritinemia-cataract syndrome (600886), resulting from a heterozygous point mutation in the L ferritin (FTL; 134790) IRE sequence, can be suspected. Hetet et al. (2003) sequenced exon 1 of the FTL gene in 52 DNA samples from patients referred for molecular diagnosis of hyperferritinemia-cataract syndrome. They identified 24 samples with a point mutation or deletion in the IRE. For the 28 samples in which no IRE mutation was present, they also genotyped for mutations in the HFE gene (613609) and sequenced both the H ferritin (FTH1; 134770) and SLC40A1 genes. They found an increased frequency (12 of 28) of heterozygotes for the HFE his63-to-asp mutation (H63D; 613609.0002), but no H ferritin mutations. They identified 3 novel SLC40A1 mutations (604653.0004-604653.0006), suggesting that these patients had dominant type 4 hemochromatosis. The study demonstrated that both L ferritin IRE and SLC40A1 mutations can account for isolated hyperferritinemia. The presence of cataract does not permit the unambiguous identification of patients with hereditary hyperferritinemia-cataract syndrome, although the existence of a family history of cataract was only encountered in these patients. This raised the possibility that lens ferritin accumulation may be a factor contributing to age-related cataract in the general population.
In transfection experiments using HEK 293T cells, De Domenico et al. (2005) showed that known human mutations introduced into the mouse Slc40a1 gene generate proteins that either are defective in cell surface localization or have a decreased ability to be internalized and degraded in response to hepcidin. Coimmunoprecipitation studies revealed that ferroportin is multimeric. Both wildtype and mutant ferroportin participated in the multimer, and mutant ferroportin affected the localization of wildtype ferroportin, its stability, and its response to hepcidin. De Domenico et al. (2005) concluded that the behavior of mutant ferroportin in cell culture and its ability to act as a dominant negative explain the dominant inheritance of the disease as well as the different patient phenotypes.
Cremonesi et al. (2005) studied 2 Italian families and 1 of Chinese descent with elevated serum ferritin levels and identified heterozygosity for 3 different mutations in the SLC40A1 gene, respectively. The authors noted the variability in phenotypes between the families and suggested that the mutation (604653.0007) in the first Italian family, in which the proband had a liver biopsy showing heavy iron deposition in both hepatocytes and Kupffer cells, likely caused decreased responsiveness to hepcidin, whereas the mutations (604653.0008 and 604653.0009) in the latter 2 families likely caused defective localization of the protein to the cell surface.
Wallace and Subramaniam (2016) reviewed 161 variants previously associated with any form of hereditary hemochromatosis and found that 43 were represented among next-generation sequence public databases including ESP, 1000 Genomes Project, and ExAC. The frequency of the C282Y mutation in HFE (613609.0001) matched previous estimates from similar populations. Of the non-HFE forms of iron overload, TFR2 (604720)-, HFE2 (608374)-, and HAMP (606464)-related forms were extremely rare, with pathogenic allele frequencies in the range of 0.00007 to 0.0005. However, SLC40A1 variants were identified in several populations (pathogenic allele frequency 0.0004), being most prevalent among Africans.
Malaria Resistance
For discussion of a possible relationship between a gln248-to-his (rs11568350) variant in the SLC40A1 gene and resistance to malaria, see 611162.
Donovan et al. (2005) found that knockout of the ferroportin gene in mice resulted in embryonic lethality, likely from a defect in iron transfer from the mother. Heterozygous animals were viable and showed a mild disruption of iron homeostasis. Mutant mice with ferroportin deleted in all tissues except extraembryonic visceral endoderm and placenta appeared normal at birth, but they developed anemia and abnormal iron accumulation in duodenal enterocytes, Kupffer cells and hepatocytes, and splenic macrophages. Mice with ferroportin deletion restricted to the intestines developed severe iron deficiency anemia. Donovan et al. (2005) concluded that ferroportin is essential for prenatal and postnatal iron homeostasis, specifically in iron transfer across extraembryonic visceral endoderm, and iron export from enterocytes, macrophages, and hepatocytes.
Zohn et al. (2007) reported the mouse flatiron (ffe) mutation, a his32-to-arg (H32R) substitution in Fpn that affected its localization and iron export activity. Similar to human patients with classic ferroportin disease, heterozygous ffe/+ mice exhibited iron loading on Kupffer cells, high serum ferritin, and low transferrin saturation. Using macrophages from ffe/+ mice and through expression of Fpn(ffe) in human embryonic kidney cells, Zohn et al. (2007) showed that Fpn(ffe) acted in a dominant-negative manner and prevented wildtype Fpn from localizing on the cell surface and transporting iron.
In a large Dutch family with autosomal dominant hemochromatosis (HFE4; 606069), Njajou et al. (2001) identified an A-to-C transversion at nucleotide 734 in exon 5 of the SLC40A1 gene, resulting in an asn144-to-his substitution.
In an Italian family, Montosi et al. (2001) determined linkage of autosomal dominant hemochromatosis (HFE4; 606069) to 2q32 and demonstrated a nonconservative missense mutation in the ferroportin gene: a GCC-to-GAC change resulting in an ala77-to-asp (A77D) substitution.
In 147 Indian patients with thalassemia major and 65 cirrhotic controls, Agarwal et al. (2006) analyzed the SLC40A1 gene and other modifier genes of iron hemostasis and identified the A77D mutation in 3 thalassemia patients, 2 heterozygotes and 1 homozygote. The mutation was not found in the control group. Agarwal et al. (2006) stated that this was the first report of a ferroportin mutation in the Indian population.
In an Australian family with autosomal dominant hemochromatosis (HFE4; 606069), Wallace et al. (2002) found heterozygosity for a 3-bp (TTG) deletion in exon 5 of the FPN1 gene, resulting in the deletion of valine at position 162. They proposed that the deletion is a loss-of-function mutation that results in impaired iron homeostasis and leads to iron overload. The mutation was present in 2 brothers in whom the diagnosis was made at ages 56 and 73 years and who had hepatic fibrosis. It was also present in the first brother's children: his son, in whom the diagnosis was made at age 20 years and who had mild fibrosis, and his daughter, age 19 years, who had no hepatic abnormality.
In the United Kingdom, Devalia et al. (2002) found the same mutation in members of a family with autosomal dominant hemochromatosis. The proband was a 38-year-old woman who presented with fatigue and was found to have a high serum ferritin concentration and, by liver biopsy, heavy iron deposition in both hepatocytes and Kupffer cells. Venesection therapy was poorly tolerated (i.e., anemia developed), suggesting a defect in iron release from reticuloendothelial stores. The proband's sister likewise had high serum ferritin concentration, and MRI suggested iron accumulation in both the liver and spleen. Liver biopsy showed no fibrosis but marked iron accumulation in Kupffer cells. The combination of erythropoietin administration with phlebotomy permitted removal of iron without anemia. Although details were not provided, other members of the family were affected in a pedigree pattern consistent with autosomal dominant inheritance.
The same heterozygous 3-bp deletion in the FPN1 gene was reported by Roetto et al. (2002) in 2 related Italian patients and in 1 unrelated British patient, suggesting that this is a particularly common mutation in type 4 hemochromatosis. Roetto et al. (2002) suggested that haploinsufficiency for ferroportin-1 would be more limiting to iron transport in reticuloendothelial cells than in duodenal enterocytes, because the flux of iron through the reticuloendothelial macrophages far exceeds the flux of iron through the duodenal mucosa.
Cazzola et al. (2002) found the same mutation in a family with autosomal dominant hyperferritinemia in whom the proband showed selective iron accumulation in the Kupffer cells on liver biopsy. The mutation occurred in the region of nucleotides 780-791, which comprises 4 TTG repeats; the loss of 1 TTG unit was predicted to result in the deletion of 1 of 3 sequential valine residues, codons 160-162. This is a recurrent mutation, presumably due to slippage mispairing. Affected individuals showed marginally low serum iron and transferrin saturation. Serum ferritin levels were directly related to age, but were 10 to 20 times higher than normal. Cazzola et al. (2002) suggested that heterozygosity for this mutation represents the prototype of selective reticuloendothelial iron overload, and should be taken into account in the differential diagnosis of hereditary or congenital hyperferritinemias, such as hyperferritinemia-cataract syndrome (600886), which is due to mutations in the ferritin light chain gene (FTL; 134790), or disorders of the ferritin heavy chain gene (FTH1; 134770).
In a patient with type 4 hemochromatosis (HFE4; 606069), Hetet et al. (2003) identified an asp157-to-gly (D157G) mutation in the SLC40A1 gene.
In a patient with type 4 hemochromatosis (HFE4; 606069), Hetet et al. (2003) identified a gln182-to-his (Q182H) mutation in the SLC40A1 gene. The patient's daughter also had increased serum ferritin levels and was found to carry the Q182H mutation.
In a patient with type 4 hemochromatosis (HFE4; 606069), Hetet et al. (2003) identified a gly323-to-val (G323V) mutation in the SLC40A1 gene.
In affected members of an Italian family with elevated serum ferritin and low hepcidin/ferritin ratios (HFE4; 606069), Cremonesi et al. (2005) identified heterozygosity for an 846A-T transversion in exon 6 of the SLC40A1 gene, resulting in an asp181-to-val (D181V) substitution. A liver biopsy from the 34-year-old male proband revealed heavy iron deposition in both hepatocytes and Kupffer cells.
In 3 affected members of an Italian family with elevated serum ferritin (HFE4; 606069), Cremonesi et al. (2005) identified heterozygosity for a 543G-T transversion in exon 3 of the SLC40A1 gene, resulting in a gly80-to-val (G80V) substitution.
In 6 affected members of family of Chinese descent with isolated elevated serum ferritin (HFE4; 606069), Cremonesi et al. (2005) identified heterozygosity for a 1104G-A transition in exon 7 of the SLC40A1 gene, resulting in a gly267-to-asp (G267D) substitution.
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